Impaired Arteriogenic Response to Acute Hindlimb Ischemia in CD4-Knockout Mice

Abstract

Background-T lymphocytes, components of the immune and inflammatory systems, are involved in such normal processes as wound healing and host defense against infection and in such pathological processes as tumor growth and atherosclerotic plaque development. Angiogenesis is a mechanism common to each. Because CD4ϩ T lymphocytes are active in regulating humoral and cellular responses of the immune system, we determined whether CD4ϩ cells contribute to collateral vessel development by using the mouse ischemic hindlimb model. Methods and Results-One week after ischemia, CD4Ϫ/Ϫ mice showed reduced collateral flow induction, macrophage number, and vascular endothelial growth factor levels in the ischemic muscle compared with wild-type mice. There was also delayed recovery of hindlimb function and increased muscle atrophy/fibrosis. Spleen-derived purified CD4ϩ T cells infused into CD4Ϫ/Ϫ mice selectively localized to the ischemic limb and significantly increased collateral flow as well as macrophage number and vascular endothelial growth factor levels in the ischemic muscle. Muscle function and damage also improved. Conclusions-These results indicate an important role of CD4ϩ cells in collateral development, as demonstrated by a 25%decrease in blood flow recovery after femoral artery ligation. Our data also suggest that CD4ϩ T cells control the arteriogenic response to acute hindlimb ischemia, at least in part, by recruiting macrophages to the site of active collateral artery formation, which in turn triggers the development of collaterals through the synthesis of arteriogenic cytokines.

Role of gp91 phox (Nox2)-Containing NAD(P)H Oxidase in Angiogenesis in Response to Hindlimb Ischemia

“…2,3,42,43 In the present study, we demonstrate that the absence of gp91 phox did not inhibit recruitment of inflammatory cells (assessed at day 3) or the increased expression of VEGF at 3 or 7 days after operation ( Figure 5). These observations are in line with previous reports that gp91 phox -knockout mice show normal inflammatory responses to bacteria 44 and to hindlimb unloading/reloading, which induces muscle inflammation.…”

“…We found that gp91 phox -derived ROS are produced mainly from inflammatory cells and neovascular ECs in early (day 3) and later phases (day 7), respectively. Acute inflammatory cell recruitment to ischemic tissue appears to be necessary 2,3,42,43 but not sufficient for the full reconstitution of blood flow at the time points studied here. Although ROS produced from infiltrated inflammatory cells may be important for the subsequent activation of ECs, induced events involving ROS production within the endothelium itself appear to be essential to the complete development of angiogenesis in response to tissue ischemia.…”

The Presence of Activated CD4+ T Cells Is Essential for the Formation of Colony-Forming Unit-Endothelial Cells by CD14+ Cells

“…The collateral-enhancing effects of CD4 ϩ T cells appear to reside in the classic immune response activity of these T cells inducing monocyte-macrophage accumulation in the ischemic muscle. The accumulating macrophages then secrete a broad array of cytokines and growth factors, which facilitate collateral development (34). These results were confirmed by Van Weel et al (35), who described a role for NK cells and CD4 ϩ T cells in arteriogenesis in knockout mice.…”

Atherosclerotic Plaque Progression and Vulnerability to Rupture

“…55 The dependency of T cells in mediating angiogenic responses was demonstrated recently in CD4 knockout mice exposed to acute hindlimb ischemia. 56 Inflammation and collateral development in response to ischemia were significantly impaired in CD4Ϫ/Ϫ versus C57BL6 wild-type mice. Moreover, rescue experiments involving the infusion of spleenderived purified CD4-positive T cells in CD4 null mice increased macrophage recruitment, resulting in blood flow recovery, limb salvage, and reduced muscle atrophy.…”